The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target.

Glutathione (GSH) is the most abundant thiol antioxidant in the human body and serves many important biochemical functions, including the regulation of vitamins, such as vitamins D, E, and C, and detoxification of drugs and toxins. As a powerful antioxidant, GSH is particularly important as a regulator of mitochondrial metabolism and a free radical scavenger that limits oxidative damage to cellular components. Low GSH levels have been associated with many chronic pro-inflammatory conditions, such as metabolic syndrome, cardiovascular, renal, and hepatic disease, as well as neurodegenerative conditions and autoimmune diseases. Given GSH's known direct protective role in mitochondrial metabolism and its association with chronic diseases of highly metabolically active tissues, this review aims to examine the literature for evidence that low GSH levels may be an important causative factor in the development of chronic illnesses. Because no large prospective human trials have been conducted using direct measurements of GSH, this review focused on the more common biomarker gamma-glutamyl transferase (GGT) which is directly correlated to low GSH levels. Several large prospective studies support this hypothesis by demonstrating that higher GGT levels are correlated with the risk of developing metabolic syndrome and cardiovascular disease in a dose-dependent fashion. Furthermore, as a corollary to this hypothesis, human and animal trials utilizing GSH augmentation using precursor supplementation in chronic conditions, including metabolic syndrome, cardiovascular disease, hepatic disease, renal disease, and neurodegenerative conditions, were also reviewed. While many of these trials were preliminary and small, there is strong evidence that GSH supplementation leads to improved outcomes in all of these chronic conditions. This review seeks to highlight these studies as preliminary evidence demonstrating the contributory role of GSH in chronic disease progression because a simple and cost-effective strategy can be created to screen for, track, and intervene in susceptible patients in the primary care setting at the earliest possible time in the disease process. Such a novel strategy would impact the majority of chronic diseases contributing to the bulk of morbidity and mortality in the Western world, and, thus, even minor benefits across many conditions may substantially impact population-wide health and longevity.

A prospective trial of intraoperative tissue oxygenation measurement and its association with anastomotic leak rate after Ivor Lewis esophagectomy.

BACKGROUND: Anastomotic leak following Ivor Lewis esophagectomy is associated with increased morbidity/mortality and decreased survival. Tissue oxygenation at the anastomotic site may influence anastomotic leak. Methods for establishing tissue oxygenation at the anastomotic site are lacking. METHODS: Over a 2-year study period, 185 Ivor Lewis esophagectomies were performed. Study participants underwent measurement of gastric conduit tissue oxygenation at the planned anastomotic site using the wireless pulse oximetry device. Associations between anastomotic leaks or strictures and tissue oxygenation levels were analyzed using Wilcoxon rank sum test or Fisher's exact test. RESULTS: Among study participants (n=114), median gastric conduit tissue oxygenation level was 92% (range, 62-100%). There were 8 (7.0%) anastomotic leaks and 3 (2.6%) strictures. Analysis of tissue oxygenation as a continuous variable showed no difference in median tissue oxygenation in patients with and without leaks (98% and 92%; P=0.2) and stricture formation (89% and 92%; P=0.6). Analysis of tissue oxygenation as a dichotomous variable found no difference in anastomotic leak rates [7.5% (n=93) in >80% vs. 0% (n=20) in ≤80%; P=0.3]. There were no significant differences in leak rates in concurrent study nonparticipants. CONCLUSIONS: No significant association was observed between intraoperative tissue oxygenation at the anastomotic site and subsequent anastomotic leak or stricture formation among patients undergoing Ivor Lewis esophagectomy.

Asynchronous Bilateral Obturator Hernias: A Suggested Approach to Reduce Morbidity of Obturator Hernias.

Obturator hernias (OHs) are rare pelvic hernias that involve the protrusion of intraperitoneal or extraperitoneal organs or tissues through the obturator foramen. Risk factors for OH patients include female gender, chronic disease, age, malnourishment, history of multiple pregnancies, anatomical enlargement of obturator foramen, increased intraabdominal pressure, and defective collagen metabolism. Since OHs have the highest mortality rate of all abdominal hernias, prompt diagnosis and treatment are critical. Prior research has demonstrated an increased likelihood of bilateral OHs relative to unilateral. We present the case of a 79-year-old female who presented with an obstructed OH six months after an operation for an OH on the contralateral side. Due to the potential morbidity and mortality associated with OHs and delay in discovery, we suggest evaluation and treatment of the contralateral side in patients who present with unilateral OHs.

Abdominal Apoplexy: A Case Study of Idiopathic Spontaneous Lesser Sac Hematoma.

Idiopathic spontaneous intraperitoneal hemorrhage (ISIH) is a rare event associated with high mortality. There have been multiple case reports of spontaneous rupture of middle colic pseudoaneurysms in the literature. Herein, we present a case of a 51-year-old female that presented with spontaneous rupture of the middle colic artery and associated massive intraabdominal hematoma without findings of a pseudoaneurysm. The patient underwent a computed tomography (CT) scan as an outpatient 24 hours prior to the onset of the bleeding due to abdominal pain without findings of hematoma or aneurysm of the mesenteric vessels. Subsequently, the patient underwent emergent exploratory laparotomy with findings of a massive hematoma in the lesser sac and spontaneous bleeding from the middle colic artery that was ligated. The patient had an uneventful postoperative course and fully recovered. To our knowledge, this is the second reported case of idiopathic bleeding from the middle colic artery without evidence of a pseudoaneurysm based on a current review of the literature.

Post Traumatic Pseudoaneurysm of Left Anterior Descending Artery Presenting as Acute Coronary Syndrome.

Penetrating cardiac injuries are highly lethal and carry high mortality rate. Both blunt and penetrating cardiac injuries in patients who survive are known to present with well-known sequelae that often appear days to weeks after the initial insult. In the literature there have been documented cases of cardiac injury induced myocardial infarction, ventricular aneurysms, valvular dysfunction and even fistulous tracts between the coronary vessels and chamber. Although the most commonly injured vessel is the left anterior descending (LAD) coronary artery, traumatic injuries to the left coronary artery result in early death in the majority of cases. We present a unique case of LAD pseudo aneurysm and stenosis presenting as acute coronary syndrome (ACS) months after the initial penetrating cardiac injury successfully managed by stenting. There are only few isolated case reports of coronary artery pseudoaneurysm following penetrating chest trauma published in English literature.

Minimally Invasive Lobectomy Is Associated With Lower Noncancer-specific Mortality in Elderly Patients: A Propensity Score Matched Competing Risks Analysis.

OBJECTIVE: To investigate cancer- and noncancer-specific mortality following lobectomy by minimally invasive surgery (MIS) versus open thoracotomy in elderly patients with nonsmall cell lung cancer (NSCLC). BACKGROUND: Two-thirds of patients with NSCLC are ≥65 years of age. As age increases, the risk of competing events, such as noncancer death, also increases. METHODS: Elderly patients (≥65 yrs of age) who have undergone curative-intent lobectomy for stage I-III NSCLC without induction therapy (2002-2013) were included (n=1,303). Of those, 607 patients had undergone MIS and 696 had undergone thoracotomy. Propensity-score matching was performed to identify pairs of thoracotomy and MIS patients with comparable clinical characteristics (eg, year of surgery, comorbidities, and pulmonary function). Association between surgical approach (MIS vs thoracotomy) and lung cancer-specific and noncancer-specific cumulative incidence of death (CID) was analyzed using competing risks approach. RESULTS: Following propensity score matching of patients who had undergone thoracotomy (n=338) versus MIS (n=338), MIS was associated with shorter length of stay (P <0.001), lower noncancer-specific 1-year mortality (P=0.027), and lower noncancer-specific CID (P=0.014) compared with thoracotomy; there was no difference in lung cancer-specific CID between surgical approaches. On multivariable analysis, thoracotomy was a significant risk factor for noncancer-specific death (subhazard ratio 2.45, 95% CI 1.18-5.06, P=0.016) independent of age, sex, and diffusion capacity of the lungs for carbon monoxide. CONCLUSION: In a propensity score-matched cohort, multivariable analysis has indicated that lobectomy performed by MIS is associated with lower incidence of noncancer-specific mortality compared with lobectomy performed by open thoracotomy in elderly patients with NSCLC.

Primary Cutaneous Follicle Center Lymphoma.

CONTEXT.­: Primary cutaneous follicle center lymphoma is a low-grade B-cell lymphoma that is limited to the skin at diagnosis. It has a differential diagnosis that includes systemic/nodal follicular lymphoma secondarily involving the skin; primary cutaneous diffuse large B-cell lymphoma leg type; reactive lymphoid hyperplasia; and primary cutaneous marginal zone lymphoma. OBJECTIVE.­: To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous follicle center lymphoma; its differential diagnosis; and the evidence that supports use of immunohistochemistry and genetic testing in the diagnosis and prognosis of this entity. DATA SOURCES.­: Pertinent literature regarding cutaneous B-cell lymphomas is summarized and University of Michigan cases are used to highlight characteristics of primary cutaneous follicle center lymphoma. CONCLUSIONS.­: Primary cutaneous follicle center lymphoma is a low-grade B-cell lymphoma with distinctive features, although some cases may have elements that overlap with other lymphomas, complicating interpretation.

Endovascular Management of a Penetrating Zone III Retroperitoneal Gunshot Wound Injury; A Case Report.

Traumatic iliac vessels injuries secondary to gunshot wound can often be fatal at the scene. One of the intriguing complications of vascular injuries is arteriovenous fistula. If the patient survives, these lesions may often not be diagnosed on first evaluation and patients may present with clinical signs and symptoms years later. Open surgical repair can have prohibitive morbidity and mortality and endovascular techniques, an effective treatment alternative, can interrupt the abnormal vascular communication and preserve artery vein patency. We describe a unique case of iliac arteriovenous fistula (AVF), secondary to a bullet injury, identified by imaging studies and subsequently treated with endovascular surgery. In conclusion, traumatic AVF are rare. Traditional teaching mandates that zone III pelvic retroperitoneal hematomas secondary to penetrating trauma be explored.

Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis.

Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non-small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer-specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer-specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer-specific mortality ( P = .002). Conclusion In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.

A Case of Spontaneous Postpartum Thyroid Hemorrhage Leading to Upper Airway Obstruction.

BACKGROUND: Spontaneous goiter hemorrhage is a rare entity that can lead to life-threatening respiratory compromise. Goiter hemorrhages are usually due to effects of anticoagulation or neoplastic processes. The hormonal effects of pregnancy may also lead to such life-threatening goiter hemorrhages in the immediate postpartum period. CASE REPORT: We report the case of a 36-year-old woman who complained of progressive neck swelling as well as eventual shortness of breath in the immediate postpartum period. Computed tomography scans and ultrasound of the neck revealed an enlarged and heterogeneous thyroid with airway compression. The patient underwent an emergent subtotal thyroidectomy to alleviate the mass effect on the airway. Upon resection, the thyroid was noted to contain a goiter hemorrhage with no signs of neoplastic degeneration on pathology. CONCLUSIONS: Pregnancy is a known hormonal stressor that routinely increases the size of the thyroid and also predisposes patients to goiter formation. In rare cases, thyroid goiters may be predisposed to hemorrhage, causing airway obstruction and necessitating urgent surgical intervention.

Prostate Cancer in Seniors: Part 1: Epidemiology, Pathology, and Screening.

Patients and clinicians should carefully weigh risk factors, life expectancy, and existing medical comorbidities when making screening and treatment decisions for prostate cancer.

Prostate Cancer in Male Seniors Part 2: Treatment.

Treatment decisions for patients with prostate cancer should be based on a patient's health status, including life expectancy, functional performance, and comorbidities.

Outcomes of adjuvant chemoradiation after pancreaticoduodenectomy with mesenterico-portal vein resection for adenocarcinoma of the pancreas.

PURPOSE: Surgery followed by chemotherapy and radiation (CRT) offers patients with pancreatic adenocarcinoma a chance for extended survival. In some patients, however, resection is difficult because of vascular involvement by the carcinoma, necessitating resection and grafting of the mesenterico-portal vessels. The purpose of this study was to compare outcomes between pancreaticoduodenectomy (PD) with and without mesenterico-portal vein resection (VR) in patients receiving adjuvant CRT for pancreatic adenocarcinoma. METHODS AND MATERIALS: Between 1993 and 2005, 160 patients underwent PD with 5-FU-based adjuvant CRT followed by maintenance chemotherapy at the Johns Hopkins Hospital; 20 (12.5%) of the 160 underwent VR. Clinical outcomes, including median survival, overall survival, and complication rates were assessed for both groups. RESULTS: Patients who underwent VR had significantly longer operative times (p = 0.009), greater intraoperative blood loss (p = 0.01), and longer postoperative lengths of stay (p = 0.03). However, postoperative morbidity, median survival, and overall survival rates were similar between the two groups. Most patients (70%) from both groups were able to complete CRT, and a subgroup analysis demonstrated no appreciable differences in terms of complications. None of the VR patients who received adjuvant CRT developed veno-oclusive disease or graft failure/leakage. CONCLUSION: In a cohort of patients treated with adjuvant 5-FU-based CRT at the Johns Hopkins Hospital, having a VR at the time of PD resulted in similar complication rates and survival. These data support the feasibility and safety of adjuvant CRT in patients undergoing VR at the time of PD.

Radiotherapeutic management of laryngeal carcinoma.

Authors discuss laryngeal lesions, metastases, and relevant anatomy. Outcome of surgical and radiotherapy in terms of voice preservation is discussed. Radiation techniques and outcomes for laryngeal cancer are presented along with discussion of interdisciplinary treatment. Authors review studies and quality of life outcomes of surviving laryngeal cancer patients.

ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.

PURPOSE: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. EXPERIMENTAL DESIGN: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. RESULTS: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. CONCLUSIONS: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.